Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.

Autor: Wang R; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Gomez Salazar M; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Pruñonosa Cervera I; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Coutts A; Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK., French K; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Pinto MM; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Gohlke S; Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany., García-Martín R; Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC (CNB-CSIC), Campus-UAM, Madrid, Spain., Blüher M; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Schofield CJ; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford, Oxford, UK., Kourtzelis I; Hull York Medical School, York Biomedical Research Institute, University of York, York, UK., Stimson RH; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Bénézech C; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Christian M; Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK., Schulz TJ; Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany., Gudmundsson EF; Icelandic Heart Association, Kopavogur, Iceland., Jennings LL; Novartis Institutes for Biomedical Research, Cambridge, MA, USA., Gudnason VG; Icelandic Heart Association, Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Chavakis T; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.; Paul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Technische Universität Dresden, Dresden, Germany., Morton NM; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.; Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK., Emilsson V; Icelandic Heart Association, Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Michailidou Z; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. zoi.michailidou@ntu.ac.uk.; Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK. zoi.michailidou@ntu.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 29; Vol. 15 (1), pp. 7483. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1038/s41467-024-51718-7
Abstrakt: Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
(© 2024. The Author(s).)
Databáze: MEDLINE
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